Johnson, Margaret A MD*; Gathe, Joseph C Jr MD†; Podzamczer, Daniel MD‡; Molina, Jean-Michel MD, PhD§; Naylor, Christian T BA‖; Chiu, Yi-Lin PhD‖; King, Martin S PhD‖; Podsadecki, Thomas J MD‖; Hanna, George J MD‖; Brun, Scott C MD‖
With the advent of highly active antiretroviral therapy in the late 1990s, morbidity and mortality related to HIV disease declined dramatically,1 essentially transforming HIV disease into a chronic illness requiring long-term management. Since the introduction of the first wave of HIV-1 protease inhibitors, attention has focused on improving the efficacy, convenience, and tolerability of this class of medications, with particular emphasis placed on reducing pill counts and dosing frequency.
Lopinavir/ritonavir has demonstrated durable antiviral activity in antiretroviral-naive and protease inhibitor-experienced patients.2-5 The soft-gelatin capsule formulation of lopinavir/ritonavir requires the administration of 3 capsules twice daily. Reducing the dosing frequency of lopinavir/ritonavir may result in greater patient convenience, which could translate into greater adherence. A high degree of adherence, in turn, has been associated with optimal efficacy of antiretroviral regimens.6,7 A pilot study evaluated the pharmacokinetics, tolerability, and efficacy of lopinavir/ritonavir administered once daily in antiretroviral-naive patients.8 Lopinavir/ritonavir was administered at a dose of 800/200 mg once daily (n = 19) or 400/100 mg twice daily (n = 19) in combination with stavudine and lamivudine, each dosed twice daily. Over 48 weeks, median predose concentrations of lopinavir exceeded the protein binding-corrected concentration required to inhibit replication of wild-type HIV-1 by 50% in vitro by 40- and 84-fold in the once-daily and twice-daily dosing groups, respectively. The lopinavir maximum concentration (Cmax) and area under the concentration-time curve at 24 hours (AUC24) values were similar between regimens. Despite the lower predose lopinavir concentrations in the once-daily group, comparable antiviral activity was observed, with 74% and 79% of patients in the once-daily and twice-daily groups, respectively, demonstrating plasma HIV-1 RNA levels <50 copies/mL at week 48 by intent-to-treat analysis. The regimens showed similar safety and tolerability.
Based on the results of the pilot study, study M02-418 was initiated to confirm the noninferior efficacy of lopinavir/ritonavir in the soft-gelatin capsule formulation administered once daily compared with twice daily in antiretroviral-naive HIV-1-infected patients and to compare the pharmacokinetics and tolerability profiles of the 2 dosing groups further. In this study, all patients also received tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) once daily; thus, the current study is not only the first trial of an entirely once-daily lopinavir/ritonavir-based regimen but is also the first clinical study to include TDF and FTC, which recently received regulatory approval as a single fixed-dose combination pill.9
Subjects were recruited from 45 centers in 7 countries in North America, Europe, Asia, and Australia. Subjects were at least 18 years old, had plasma HIV-1 RNA levels of at least 1000 copies/mL, and had no more than 7 days of any prior antiretroviral treatment. There was no CD4 cell count restriction. Patients who had been treated for an active opportunistic infection within 30 days before screening or who had an alanine aminotransferase and/or aspartate aminotransferase level greater than 3 times the upper limit of normal at screening and women who were pregnant or breast-feeding were excluded from participation. All subjects gave written informed consent, which was approved by the institutional review board or ethics committee at each of the participating institutions.
For this randomized, open-label, comparative study, the primary outcome measure was the proportion of subjects with plasma HIV-1 RNA levels less than 50 copies/mL at 48 weeks. Secondary efficacy outcomes included the proportion achieving plasma HIV-1 RNA levels less than 50 copies/mL through 48 weeks using the US Food and Drug Administration (FDA) time to loss of virologic response (TLOVR) algorithm10 and the mean change from baseline in CD4 cell count. Safety was assessed by comparing the frequency and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory values between treatment groups.
Subjects were centrally randomized at a 3:2 ratio to receive open-label lopinavir/ritonavir soft-gelatin capsules at a dose of 800/200 mg administered once daily (n = 120) or 400/100 mg administered twice daily (n = 80). Because the 400/100-mg twice-daily regimen had been extensively studied, the 3:2 randomization was designed to provide greater experience with the 800/200-mg once-daily regimen without a substantial reduction in power compared with a 1:1 randomization. All subjects also received open-label TDF tablets at a dose of 300 mg once daily and FTC capsules at a dose of 200 mg once daily. Randomization was stratified by participation in an optional pharmacokinetic subgroup evaluation, with 24 subjects (once-daily dose group) and 16 subjects (twice-daily dose group) planned to be enrolled.
Assessment and Monitoring
Subjects were evaluated at screening, day −7, baseline, week 4, week 8, and every 8 weeks through week 48. At each visit, a history was taken and a physical examination was conducted. Plasma HIV-1 RNA measurements (Roche Amplicor HIV-1 Monitor assay, version 1.5 [F. Hoffman-La Roche Ltd., Basel, Switzerland]; limit of quantitation = 50 copies/mL), CD4 and CD8 cell counts, and hematologic and clinical chemistry evaluations were obtained, and vital signs were recorded at all visits. Subjects were evaluated at baseline for infection with hepatitis B virus (HBV; detection of hepatitis B surface antigen [HBsAg+] in plasma) and hepatitis C virus (HCV; detection of antibodies to HCV). Specimens for laboratory analyses were to be obtained fasting at baseline, week 24, and week 48. For all study subjects, predose or trough plasma samples were obtained at weeks 4, 8, 16, 24, and 48. In a subset of subjects, plasma samples were collected at week 4 for pharmacokinetic analyses of lopinavir and ritonavir concentrations over the course of a 24-hour dosing interval for the once-daily dose group and over the course of a 12-hour dosing interval after the morning dose for the twice-daily dose group.
Viral Drug Resistance
Any specimen with a plasma HIV-1 RNA level >500 copies/mL from week 12 through week 48 was submitted for viral genotypic (GeneSeq; ViroLogic, Inc., South San Francisco, CA) and phenotypic resistance (PhenoSense; ViroLogic, Inc.) analysis. Analysis was also conducted on corresponding baseline specimens. Resistance to lopinavir was defined conservatively as the development of any mutation at protease amino acid 8, 30, 32, 46, 47, 48, 50, 82, 84, or 90,11 with a corresponding decrease in phenotypic susceptibility to lopinavir of at least 2.5-fold compared with wild-type HIV-1. Resistance to TDF was defined as the emergence of any new mutation at reverse transcriptase amino acid 41, 65, 67, 70, 210, 215, 219 or an insertion mutation in the vicinity of codon 69. FTC resistance was defined as the emergence of the M184V/I mutation in reverse transcriptase. For subjects with multiple postbaseline genotypic results, if any isolate from that subject met resistance criteria, resistance was considered to be present in that subject.
The planned sample size of 200 subjects provided approximately 80% power, at the 0.05 level of significance, to detect a 25% decrease in the lopinavir concentration at time 0 (before morning dose, trough concentration [Ctrough]) central value for the once-daily group compared with the twice-daily group. The sample size also provided greater than 60% power to determine noninferiority of the once-daily regimen compared with the twice-daily regimen in the primary efficacy analysis, based on a noninferiority margin of 15% and a week 48 response rate of 70% in each arm.
The proportion of subjects with plasma HIV-1 RNA values less than 50 copies/mL was summarized and compared between treatment groups using the Fisher exact test. Subjects who discontinued before week 48 were considered to have plasma HIV-1 RNA values greater than 50 copies/mL, as were subjects with missing HIV-1 RNA values, unless the immediately preceding and immediately following values were less than 50 copies/mL (intent-to-treat noncompleter = failure analysis). The 95% confidence interval for the difference in response proportions was calculated based on the normal approximation to the binomial distribution.
Pharmacokinetic parameters for lopinavir and ritonavir were determined at steady state (week 4) using the noncompartmental methods for a subset of subjects with intensive blood sample collections. Parameters included observed Cmax, time to observed maximum concentration (Tmax), Ctrough, minimum concentration (Cmin) over the dosing interval, and area under the concentration-time curve (AUC) by use of the linear trapezoidal rule from 0 to 12 hours and the log-linear trapezoidal rule from 12 to 24 hours. The AUC24 was estimated for the twice-daily regimen by multiplying the AUC over the course of a 12-hour dosing interval by 2. In addition, the inhibitory quotient (IQ), the ratio of Ctrough to the lopinavir median inhibitory concentration (IC50) in 50% human serum for wild-type HIV-1 (0.07 mg/mL), selected on the basis of the susceptibility of 3 laboratory strains,12 was determined for weeks 4, 8, 16, 24, and 48 for all subjects. Overall median lopinavir Ctrough and IQ values from weeks 4 through 48 were calculated by taking the median of all observations within each subject, followed by a median across all subjects. All trough samples were included in the analysis except those that were obtained after a missed dose (>40 hours or >20 hours after the last dose for the once-daily and twice-daily regimens, respectively).
The relation between virologic response and Ctrough and baseline disease characteristics was assessed by logistic regression.
The rates of incidence of resistance emergence and adverse events were compared by the Fisher exact test. Adverse events were graded by the investigator as “mild” (transient and easily tolerated), “moderate” (causes discomfort and disrupts usual activities), or “severe” (causes considerable interference with usual activities and may be incapacitating or life threatening). A 1-way analysis of variance was used to evaluate mean changes from baseline. A retrospective analysis of individual subject lipid changes was conducted, based on National Cholesterol Education Program Adult Treatment Panel III classifications13; because no important differences were observed between treatment groups, the groups were combined for analysis.
All statistical tests were 2-tailed and conducted at the 0.05 level of significance, using release 6.12 of the SAS System (SAS Institute, Inc., Cary, NC). All subjects who received at least 1 dose of study drug were included in the analysis, and subjects were analyzed according to their randomized treatment group.
Baseline Characteristics and Subject Disposition
Of 244 subjects screened, 196 met eligibility criteria and were randomized between August 7, 2002 and December 3, 2002 (Fig. 1). Three subjects assigned to each regimen never received study drug; the remaining 190 subjects (115 in the once-daily group and 75 in the twice-daily group) were included in the analysis. One subject in the once-daily group self-switched from once-daily to twice-daily dosing of lopinavir/ritonavir from week 32 to week 48. Baseline characteristics were similar in the 2 treatment groups (Table 1). A total of 23 subjects (20%) in the once-daily group and 22 subjects (29%) in the twice-daily group discontinued the study through week 48 (Table 2). More subjects in the twice-daily group (8%) were lost to follow-up compared with the once-daily group (3%), and discontinuation attributable to adverse events was more common in the once-daily group (12%) compared with the twice-daily group (8%), although neither difference was statistically significant. Adverse events resulting in discontinuation were generally gastrointestinal in nature.
Results of week 4 steady-state lopinavir pharmacokinetic parameters for 37 subjects are presented (Table 3). Among the parameters tested, Ctrough and Cmin were statistically significantly lower during once-daily dosing compared with twice-daily dosing (P < 0.003). Neither lopinavir AUC24 nor Cmax was statistically significantly different between the regimens (P = 0.113 for Cmax and 0.176 for AUC24). The overall median IQ was significantly lower for the once-daily group (48.1) compared with the twice-daily group (86.5; P < 0.001), corresponding to a Ctrough of 4.37 and 6.64 μg/mL, respectively.
In the primary analysis at week 48, 81 (70%) of 115 subjects in the once-daily group and 48 (64%) of 75 of subjects in the twice-daily group demonstrated plasma HIV-1 RNA levels less than 50 copies/mL (P = 0.43; Fig. 2). The 95% confidence interval for the difference (once daily − twice daily) in response was −7% to 20%. Results were similar for the secondary end point based on the FDA TLOVR algorithm, because 82 (71%) of 115 subjects in the once-daily group and 49 (65%) of 75 subjects in the twice-daily group achieved HIV-1 RNA levels less than 50 copies/mL through week 48 (P = 0.42; 95% confidence interval: −8% to 20%).
Based on logistic regression analysis, there was no statistically significant association between virologic response and lopinavir median Ctrough. Response was not dependent on demographic characteristics (gender, race/ethnicity, and age) and baseline disease characteristics (HIV-1 RNA level, CD4 cell count, and baseline hepatitis infection status) for all subjects combined or separately within each treatment group (data not shown).
Viral Drug Resistance
Twenty-two subjects (11 in the once-daily group, 11 in the twice-daily group) met criteria for genotypic resistance testing. For one subject in the twice-daily group, no specimen was available for testing; of note, the subject continued on the same regimen, and the plasma HIV-1 RNA level was subsequently less than 50 copies/mL at week 48. In 6 subjects (3 in the once-daily group, 3 in the twice-daily group), resistance testing failed because of low HIV-1 RNA levels (median = 625 copies/mL, range: 533-1029 copies/mL). Results were therefore available for 15 subjects, representing 8 subjects in the once-daily group and 7 in the twice-daily group. No subject in either group demonstrated lopinavir or TDF resistance. Development of FTC resistance was observed in 2 subjects in the once-daily group and in 1 subject in the twice-daily group.
Significant mean increases from baseline in CD4 cell count were observed at all visits for each treatment group, with no significant differences between treatment groups. The mean increases from baseline to week 48 were 185 and 196 cells/mm3 for the once-daily and twice-daily groups, respectively (P = 0.67).
The most common adverse events of at least moderate severity and with a possible, probable, or unknown relation to study drug were gastrointestinal in nature (Table 4). Nine subjects in the once-daily group (8%) and 2 in the twice-daily group (3%) discontinued the study because of gastrointestinal adverse events. Diarrhea of moderate or greater severity occurred more frequently in the once-daily group (16%) compared with the twice-daily group (5%; P = 0.036). Diarrhea generally occurred early and was self-limiting; for most of the subjects with diarrhea (12 of 22 subjects), initial onset was during the first week, and only 3 subjects had new onset events after week 16. From weeks 16 to 48, the prevalence of diarrhea remained at 6% or less in the once-daily group and at 2% or less in the twice-daily group, which includes subjects with diarrhea ongoing at the time of discontinuation.
There was 1 death in the study. A subject in the twice-daily group died of multiorgan failure after 6 weeks on study, after a diagnosis of adenocarcinoma. The subject was receiving chronic prednisone therapy for myositis. The event was considered unrelated to study drugs.
Statistically significant increases in total cholesterol were composed of significant increases in high-density lipoprotein (HDL) cholesterol (0.1 mmol/L [3 mg/dL] in the once-daily group and 0.2 mmol/L [6 mg/dL] in the twice-daily group) and low-density lipoprotein (LDL) cholesterol (0.4 mmol/L [14 mg/dL] in each group). Lipid increases were observed early, in the first 8 weeks, with little change in mean values subsequent to that time. Week 48 median values for total cholesterol and LDL cholesterol were 4.6 and 2.7 mmol/L, respectively (179 and 106 mg/dL, respectively), for the once-daily group and 4.8 and 3.0 mmol/L, respectively (187 and 117 mg/dL, respectively), for the twice-daily group. Week 48 median triglyceride values were 1.9 mmol/L (172 mg/dL) in the once-daily group and 2.0 mmol/L (176 mg/dL) in the twice-daily group. Three subjects were using lipid-lowering agents at baseline, and 1 additional subject in each treatment group initiated lipid-lowering agents during the first 48 weeks of the study.
In an analysis of combined treatment groups, 86% of subjects had LDL cholesterol levels in the optimal or near-optimal range (<130 mg/dL or 3.37 mmol/L)13 at baseline, compared with 74% at week 48. For HDL cholesterol, the proportion of subjects with low values (<40 mg/dL or 1.04 mmol/L) decreased from 58% at baseline to 42% at week 48, whereas the proportion of subjects with high values (≥60 mg/dL or 1.55 mmol/L) increased from 8% to 13% over the same period. Grade 3 or higher elevations of total cholesterol (>300 mg/dL or 7.77 mmol/L) and triglycerides (>750 mg/dL or 8.47 mmol/L) were uncommon and occurred in less than 3% and 5% of subjects in either group, respectively (see Table 4). At week 48, 87% of subjects maintained grade 0 to 1 or lower values for total cholesterol (<240 mg/dL or 6.22 mmol/L) and triglycerides (<400 mg/dL or 4.52 mmol/L).
Small but statistically significant increases in mean serum creatinine were observed from baseline (0.86 mg/dL) to week 48 (0.91 mg/dL; P < 0.001), with no statistically significant difference between groups. Decreases in creatinine clearance, as estimated by the Cockcroft-Gault equation (120 mL/min at baseline, 112 mL/min at week 48; P < 0.001), and glomerular filtration rate, as estimated by the modification on diet in renal disease (MDRD) equation (112 mL/min/1.73 m2 at baseline, 104 mL/min/1.73 m2 at week 48; P < 0.001), were also observed with no statistically significant differences between the once-daily and twice-daily groups.
Overall, for 98% of subjects, the maximum creatinine value was ≤1.5 mg/dL. One subject in each group demonstrated a creatinine value >3.0 mg/dL and acute renal failure (ARF). ARF occurred at week 38 in a 54-year-old male subject with a history of diabetes mellitus and a baseline creatinine clearance of 114 mL/min, who required temporary hemodialysis. Renal biopsy demonstrated interstitial nephritis. The subject discontinued the study, and creatinine levels returned to near normal. ARF also occurred at week 34 in a 75-year-old male subject with a history of diabetes mellitus and a baseline creatinine clearance of 40 mL/min, who was begun on full-dose TDF. The subject received 1 hemodialysis session. Renal biopsy demonstrated signs compatible with diabetic nephropathy. Lopinavir/ritonavir was restarted, but TDF was replaced by stavudine at a dose of 30 mg administered twice daily and the dose of FTC was reduced to 200 mg every 72 hours. His creatinine level continued to decrease to near-normal levels. TDF dosing recommendations implemented after initiation of this study indicate that administration of TDF every other day would have been most appropriate for this subject based on creatinine clearance.
Prior studies have demonstrated that lopinavir/ritonavir at a dose of 400/100 mg administered twice daily in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) provides a potent, well-tolerated, and durable treatment regimen for antiretroviral naive patients.2,3 In this clinical trial conducted in previously untreated HIV-1-infected individuals, an entirely once-daily regimen consisting of the lopinavir/ritonavir soft-gelatin capsule at a dose of 800/200 mg with TDF and FTC was noninferior to lopinavir/ritonavir at a dose of 400/100 mg administered twice daily with the same NRTI backbone. In the primary analysis at week 48, 70% of subjects in the once-daily group and 64% of subjects in the twice-daily group demonstrated HIV-1 RNA levels less than 50 copies/mL. The lower bound of the 95% confidence interval for the difference (once daily − twice daily) falls at −7%, which is well within the −10% to −12% boundary commonly accepted as establishing noninferiority for antiretroviral treatment regimens administered to subjects new to therapy.10 Immunologic recovery, as measured by CD4 cell increases from baseline, was similar in the 2 treatment arms.
These regimens using the soft-gelatin capsule formulation of lopinavir/ritonavir were safe and relatively well tolerated. Overall discontinuations were similar between groups, although a greater number of discontinuations for adverse events (primarily gastrointestinal) and a significantly higher rate of diarrhea were observed in the once-daily group. No significant difference in lipid profiles was observed between the once-daily and twice-daily groups. LDL cholesterol effects were modest in both groups, with findings suggesting that only an additional 12% of the study population shifted out of the optimal LDL cholesterol range (<130 mg/dL or 3.37 mmol/L)13 during 48 weeks of therapy. Additionally, HDL cholesterol increases were observed in both groups. The most pronounced lipid effect was observed with respect to triglycerides. Almost 90% of subjects maintained triglyceride values <400 mg/dL (4.52 mmol/L), however. In this study, the lipid increases were less than have been observed when lopinavir/ritonavir is administered with thymidine analogue nucleosides, such as stavudine.3 The use of lipid-lowering agents was uncommon in both study arms, and no subject discontinued the study because of lipid elevations.
The distribution of creatinine values observed was comparable to that reported in earlier trials with TDF.14 Two subjects developed ARF during the first 48 weeks of the study. The clinical presentation and pathophysiologic mechanism leading to renal failure seem to differ in these 2 subjects. Therefore, these cases did not seem to represent an aggregate signal for synergistic renal toxicity attributable to coadministration of lopinavir/ritonavir and TDF.
Despite differences in the NRTI backbone, pharmacokinetic results observed in this study (using once-daily TDF and FTC) were consistent with observations made in a prior pilot study evaluating once-daily lopinavir/ritonavir (and using an NRTI backbone of twice-daily stavudine and lamivudine) in HIV-1-infected subjects.8 Thus, there is no evidence to suggest that these different NRTI backbones affect lopinavir plasma concentrations differently. Additionally, although the Ctrough achieved with lopinavir with once-daily dosing is significantly lower than that achieved with twice-daily dosing, a pharmacokinetic/pharmacodynamic analysis did not suggest an association of a lower lopinavir Ctrough with reduced virologic response in this study. This observation suggests that for antiretroviral-naive patients, the Ctrough of lopinavir achieved with the once-daily dosing regimen does not reside on the steep portion of the concentration-response curve. The lack of development of lopinavir resistance in either dosing group and the low rate of FTC resistance through 48 weeks of therapy further support this theory and suggest that the subsequent use of protease inhibitor-based treatment regimens would not be limited through the use of either lopinavir/ritonavir dosing schedule as initial therapy for HIV-1. The absence of resistance in this study is also consistent with reports that boosted protease inhibitor-based regimens are associated with lower rates of resistance than nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.15
Certain limitations of this study should be considered. The sample size provided only 60% power to determine noninferiority of the once-daily group in the primary efficacy analysis, typical of a phase 2b study but lower than the 80% to 90% power used in phase 3 studies. Power calculations are of less interest once a trial is complete, however; in particular, the study results demonstrated noninferiority of the 2 regimens despite the prestudy power calculations.16 With any noninferiority study, the performance of the control arm may also limit interpretation. Notably, the lopinavir/ritonavir-based twice-daily reference arm in this study performed similar to a lopinavir/ritonavir-based twice-daily regimen evaluated in a large, double-blind, randomized, controlled phase 3 study (67% <50 copies/mL at week 48),3 indicating that the twice-daily dose arm in this study provided a valid control group. Although no difference was seen in efficacy between the once-daily and twice-daily groups through 48 weeks, the analysis does not address the impact that lower Ctrough and IQ might have on longer term follow-up.
With the increasing number of available once-daily NRTIs, interest in once-daily protease inhibitor-based regimens is likely to grow. More convenient treatment regimens may lead to improved patient adherence, and thus to improved long-term efficacy. Results of the current study suggest that once-daily dosing of lopinavir/ritonavir is a suitable option for antiretroviral-naive patients initiating HIV-1 therapy. The new lopinavir/ritonavir tablet formulation (reduced pill count from 6 capsules to 4 tablets per day, reduced pharmacokinetic variability, no need for refrigerated storage, and dosed without regard to meals) may have fewer gastrointestinal adverse effects17 and may further increase the convenience of a lopinavir-based once-daily regimen for patients.
The authors express their gratitude and appreciation to the subjects who participated in this study. They also acknowledge the invaluable support of the investigators, study coordinators, and support personnel at the study sites. In addition, the authors recognize Dr. Elena Ferrer (DP), Bénédicte Loze (JM), and Kathryn R. King (SCB) for their contributions to this study and the manuscript. Gilead Sciences, Inc. provided TDF and FTC.
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3. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346:2039-2046.
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5. Kempf DJ, Isaacson JD, King MS, et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther. 2002;7:165-174.
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9. Truvada (emtricitabine/tenofovir disoproxil fumarate) currently approved prescribing information for Australia, Canada, EU and the US. Gilead Sciences, Inc., Foster City, CA, 2006.
10. US Department of Health and Human Services Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for Industry-Antiretroviral Drugs Using Plasma HIV RNA Measurements-Clinical Considerations for Accelerated and Traditional Approval. 2002.
11. Hirsch MS, Brun-Vezinet F, D'Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA. 2000;283:2417-2426.
12. Molla A, Vasavanonda S, Kumar G, et al. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology. 1998;250:255-262.
13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
14. Viread (tenofovir disoproxil fumarate) currently approved prescribing information for Australia, Canada, EU and the US. Gilead Sciences, Inc., Foster City, CA, 2006.
15. Bartlett JA, Buda JJ, von Scheele B, et al. Minimizing resistance consequences after virologic failure on initial combination therapy: a systematic overview. J Acquir Immune Defic Syndr. 2006;41:323-331.
17. Awni W, Chiu Y-L, Braun N, et al. Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation [abstract WeOa0206]. Presented at: Third International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005; Rio de Janeiro.
© 2006 Lippincott Williams & Wilkins, Inc.